Bisimide compounds

ABSTRACT

A compound of formula (I) ##STR1## in which: X and Y, which may be identical or different, represent hydrogen or halogen or alkyl, trihaloalkyl, alkoxy, hydroxyl, cyano, nitro, amino, alkylamino, or dialkylamino, 
     Z represent a linear or branched C 4  to C 12  alkylene chain in which one or more --CH 2  -- are optionally replaced by any one of the following atoms or groups: --NR--, --O--, --S--, --SO--, --SO 2  --, or --CONH--, 
     A forms, with two adjacent carbon atoms of the phenyl ring, a phenyl, naphthyl or tetrahydronaphthyl ring or a heterocycle, ##STR2## represents any one of the groups as defined in the description, its optical isomers and its addition salts with a pharmaceutically-acceptable acid or base, and medicinal products containing the same which are useful as anticancer agents.

The present invention relates to new bisimide compounds.

BACKGROUND OF THE INVENTION

Compounds derived from bisimides have already been described in theliterature. This is more particularly the case for the compoundsdescribed in patents EP 506 008, DE 4034687, WO 9500490 or DE 4232739.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention have entirely original structurescompared with those described in the prior art. They are eithersymmetrical or dissymmetrical compounds which have never been describedpreviously. Moreover, the power of their pharmacological activitiesmakes them particularly advantageous as new drugs that are useful in thetreatment of cancers and in particular solid tumors.

More specifically, the present invention relates to the compounds offormula (I) ##STR3## in which: m, and n, which may be identical ordifferent, represent 0 or 1,

X and Y, which may be identical or different, represent a hydrogen orhalogen atom or a linear or branched (C₁ -C₆) alkyl, linear or branched(C₁ -C₆) trihaloalkyl, linear or branched (C₁ -C₆) alkoxy, hydroxyl,cyano, nitro, amino, alkylamino or dialkylamino group,

Z represent a linear or branched C₄ to C₁₂ alkylene chain in which oneor more --CH₂ -- groups are optionally replaced by any one of thefollowing atoms or groups: --NR-- (in which R represents a hydrogen atomor a linear or branched (C₁ -C₆) alkyl group), --O--, --S--, --SO--,--SO₂ --, or --CONH--, or by a substituted or unsubstituted heterocyclicgroup,

A forms, with two adjacent carbon atoms of the phenyl ring:

a substituted or unsubstituted phenyl ring,

a substituted or unsubstituted naphthyl ring,

a substituted or unsubstituted tetrahydronaphthyl ring or substituted orunsubstituted 1,4-dioxo-1,2,3,4-tetrahydronaphthyl ring,

or a substituted or unsubstituted heterocycle, ##STR4## represents anyone of the following groups: ##STR5## in which: m₁ and n₁, which may beidentical or different, represent 0 or 1,

X₁ and Y₁, which may be identical or different, represent a hydrogen orhalogen atom or a linear or branched (C₁ -C₆) alkyl, linear or branched(C₁ -C₆) trihaloalkyl, linear or branched (C₁ -C₆) alkoxy, hydroxyl,cyano, nitro, amino, alkylamino or dialkylamino group,

A₁ forms, with two adjacent carbon atoms of the phenyl ring:

a substituted or unsubstituted phenyl ring,

a substituted or unsubstituted naphthyl ring,

a substituted or unsubstituted tetrahydronaphthyl ring or substituted orunsubstituted 1,4-dioxo-1,2,3,4-tetrahydronaphthyl ring, or

a substituted or unsubstituted heterocycle, ##STR6## in which X₂, andY₂, which may be identical or different, represent a hydrogen or halogenatom or a linear or branched (C₁ -C₆) alkyl, linear or branched (C₁ -C₆)trihaloalkyl, linear or branched (C₁ -C₆) alkoxy, hydroxyl, cyano,nitro, amino, alkylamino or dialkylamino group,

their isomers and their addition salts with a pharmaceuticallyacceptable acid or base.

Among the pharmaceutically acceptable acids which may be mentioned,without any limitation being implied, are hydrochloric acid, hydrobromicacid, sulfuric acid, phosphonic acid, acetic acid, trifluoracetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,oxalic acid, methanesulfonic acid, camphoric acid, etc.

Among the pharmaceutically acceptable bases which may be mentioned,without any limitation being implied, are sodium hydroxide, potassiumhydroxide, triethylamine, tert-butylamine, etc.

The terms substituted or unsubstituted phenyl group, substituted orunsubstituted naphthyl group and substituted or unsubstitutedtetrahydronaphthyl group are understood to refer to a phenyl, naphthylor tetrahydronaphthyl group which is optionally substituted with one ormore halogen atoms or linear or branched (C₁ -C₆) alkyl, linear orbranched (C₁ -C₆) trihaloalkyl, linear or branched (C₁ -C₆) alkoxy,hydroxyl, nitro or cyano groups or amino groups (optionally substitutedwith one or more linear or branched (C₁ -C₆) alkyl groups).

The term substituted or unsubstituted heterocycle is understood to referto a mono- or bicyclic, saturated or unsaturated 5- to 16-membered groupcontaining 1, 2 or 3 hetero atoms chosen from oxygen, nitrogen andsulfur, it being understood that the heterocycle may optionally besubstituted with one or more halogen atoms or linear or branched (C₁-C₆) alkyl, linear or branched (C₁ -C₆) alkoxy, hydroxyl, trihalomethyl,nitro or cyano groups or amino groups (optionally substituted with oneor more linear or branched (C₁ -C₆) alkyl groups).

The preferred compounds according to the invention are those in which:

A forms, with two adjacent carbon atoms of the phenyl ring:

a substituted or unsubstituted naphthyl ring,

or a substituted or unsubstituted heterocycle preferably chosen fromsubstituted or unsubstituted indole, substituted or unsubstituted benzob!thiophene and substituted or unsubstituted benzo b!furan rings.

The preferred consitutents are those for which Z represents a C₄ to C₁₂alkylene chain in which 1, 2 or 3 --CH₂ -- groups are replaced by 1, 2or 3 --NR-- groups (in which R represents a linear or branched (C₁ -C₆)alkyl group).

The invention also covers the process for the preparation of thecompounds of formula (I), which process uses, as starting material, ananhydride of formula (II): ##STR7## in which A, X, Y, m and n are asdefined in formula (I), which is reacted with an excess of a diamine offormula (III):

    H.sub.2 N--Z--NH.sub.2                                     (III)

in which Z is as defined in formula (I), in order to lead, afterseparation:

either to the compound of formula (I/a), a specific case of thecompounds of formula (I): ##STR8## in which A, X, Y, Z, m and n have thesame meaning as in formula (I), or to the compound of formula (IV):##STR9## in which A, X, Y, Z, m and n have the same meaning as informula (I), which is reacted:

either with the anhydride of formula (II/a) ##STR10## in which A₁, X₁,Y₁, m₁ and n₁ are as defined in formula (I), in order to lead to thecompound of formula (I/b), a specific case of the compounds of formula(I): ##STR11## in which A, X, Y, m, n, Z, A₁, X₁, Y₁, m₁, and n₁, havethe same meaning as in formula (I),

or with the anhydride of formula (V) ##STR12## in which X₂ and Y₂ are asdefined in formula (I), in order to lead to the compound of formula(I/c), a specific case of the compounds of formula (I): ##STR13## inwhich A, X, Y, X₂, Y₂, Z, m and n have the same meaning as in formula(I), which compound of formula (I/a), (I/b) or (I/c), may undergo, if sodesired, standard reactions for the transformation of substituents onaromatic rings, which is purified, where appropriate, according to astandard purification technique, the isomers of which are optionallyseparated according to a standard separation technique and which isconverted, if so desired, into its additon salts with a pharmaceuticallyacceptable acid or base.

The anhydrides of formula (II) or (V) are either commercial compounds orare obtained according to known procedures.

The invention also covers pharmaceutical compositions containing, asactive principle, at least one compound of formula (I) with one or moreinert, non-toxic, suitable excipients. Among the pharmaceuticalcompositions according to the invention which may be mentioned moreparticularly are those which are suitable for oral, parenteral(intravenous or subcutaneous) or nasal administration, simple orsugar-coated tablets, sublingual tablets, gelatin capsules, lozenges,suppositories, creams, ointments, dermal gels, injectable preparations,drinkable suspensions, etc.

The appropriate dosage may be adapted according to the nature andseverity of the complaint, the route of administration and the age andweight of the patient. This dosage ranges from 0.1 to 400 mg per day inone or more dosage intakes.

The examples which follow illustrate the invention without, however,limiting it in any way.

The starting materials used are known products or are prepared accordingto known procedures.

The following preparations lead to synthetic intermediates that areuseful for the preparation of compounds of the invention.

The structures of the compounds described in the examples and thepreparations were determined according to the usual spectrophotometrictechniques (infrared, NMR, mass spectrometry, etc.).

PREPARATION A 10-Methoxy-2-oxacyclopenta c!phenanthrene-1,3-dione

Stage A: 2-Hydroxymethylene-7-methoxy-3,4-dihydro-2H-naphthalen-1-one

The expected product is prepared from 7-methoxy-1-tetralone and ethylformate according to the procedure described in Organic Synthesis 1959,39, 27.

Stage B: tert-Butyl3-(7-methoxy-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)-propionate

90 ml of a solution of 5 mmol of the product prepared in the above stepand 6 mmol of tert-butyl triphenylphosphoranylideneacetate in methylenechloride is stirred for 2 hours at room temperature and under argon. Themedium is concentrated under vacuum and the residue is crystallized fromisopropyl ether. The precipitate is filtered off and the filtrate isconcentrated to give 95% of a yellow product which crystallizes.

Melting point: 76° C.

Stage C: 9-Methoxy-5,6-dihydrobenzo h!-chromen-2-one

6.5 ml of trifluoracetic anhydride and then 3.6 ml of trifluoraceticacid are added dropwise at room temperature to 10 ml of a solution of4.6 mmol of the product prepared in the above stage in methylenechloride. The medium is then stirred for 4 hours, after which it ishydrolyzed with 30 ml of water. The aqueous phase is extracted with 30ml of methylene chloride and the organic phase is washed with water,dried and concentrated under vacuum.

Melting point: 108°-110° C.

Stage D: Dimethyl 6-methoxy-9,10-dihydrophenanthrene-3,4-dicarboxylate

A solution of 5.3 mmol of the product prepared in the above stage and2.6 ml of methyl acetylenedicarboxylate in 20 ml of dimethylformamide ismaintained at reflux for 4 hours. The solvent is evaporated off undervacuum and the medium is poured into 40 ml of water and extracted with 3times 10 ml of ether. The combined organic phases are washed with waterand dried over magnesium sulfate. After evaporation of the solvent, theproduct is obtained, which crystallizes.

Melting point: 158°-160° C.

Stage E: Dimethyl 6-methoxyphenanthrene-3,4-dicarboxylate

The product prepared in the above stage is dissolved in 150 ml of drytoluene. 1.2 equivalents of dichlorodicyanoquinone are added and themedium is maintained at reflux for 4 hours. After cooling, the medium isfiltered and the filtrate is evaporated. The residue is then taken up in50 ml of water and the crude product is extracted with 3 times 10 ml ofether. After concentration of the solvent, the product is purified bychromatography on silica with CH₂ CI₂ eluent.

Melting point: 112°-115° C.

Stage F: Methyl 4-methoxycarbonyl-6-methoxyphenanthrene-3-carboxylateand methyl 3-methoxycarbonyl-6-methoxyphenanthrene-4-carboxylate

A solution of the product prepared in the above step in 15 ml of 1Nsodium hydroxide and 20 ml of methanol is maintained at reflux for 3hours. After cooling, the methanol is evaporated off and the aqueousphase is acidified with 6N hydrochloric acid. The medium is extractedwith 3 times 20 ml of methylene chloride and the products are obtainedafter evaporation of the solvent.

Stage G: 10-Methoxy-2-oxacyclopenta c!phenanthrene-1,3-dione

A mixture of the acids prepared in the above step in 120 ml of aceticanhydride is maintained at reflux for 24 h. After cooling, theprecipitate is filtered off, washed with ether and dried.

Melting point: 238° C.

PREPARATION B 2-Oxacyclopenta c!phenanthrene-1,3-dione

Stage A: Dimethyl phenanthrene-3,4-dicarboxylate

A solution of 65 mmol of 2-vinylnaphthalene and 68 mmol of methylacetylene-dicarboxylate in 200 ml of nitrobenzene is maintained atreflux for 14 hours. After distillation of the solvent, the reactionmedium is chromatographed on silica (eluent: CH₂ Cl₂) in order to obtainthe expected product.

Melting point: 117° C.

Stage B: 3-Methoxycarbonylphenanthrene-4-carboxylic acid and4-methoxy-carbonylphenanthrene-3-carboxylic acid

The mixture is prepared from the product described in stage A accordingto the process described in stage F of preparation A.

Melting point: 257° C.

Stage C: 2-Oxacyclopenta c!phenanthrene-1,3-dione

The expected product is prepared from the mixture described in the abovestage according to the process described in stage G of preparation A.

Melting point: 245° C.

PREPARATION C Naphtho 2,3-c!furan-1,3-dione

The expected product is obtained according to the process described instage G of preparation A, starting with naphthalene-2,3-dicarboxylicacid.

PREPARATION D 2-Oxa-8-thiadicyclopenta a,h!naphthalene-1,3-dione

The expected product is obtained according to the process described inpreparation A, using 6,7-dihydro-5H-benzo b!thiophen-4-one in stage A.

PREPARATION E 9-Aza-9,10-dimethyl-6-methoxy-2-oxa-9H-cyclopentab!fluorene-1,3-dione

Stage A: Dimethyl 1,9-dimethyl-6-methoxy-9H-carbazole-2,3-dicarboxylate

The expected product is prepared from 1,9-dimethyl-6-methoxy-9H-pyrano3,4-b!indol-3-one according to the method described in Chem. Ber, 97,667, 1964.

Stage B:1,9-Dimethyl-6-methoxy-2-methoxycarbonyl-9H-carbazole-3-carboxylic acidand 1,9-dimethyl-6-methoxy-3-methoxycarbonyl-9H-carbazole-2-carboxylicacid

The mixture is prepared from the product described in stage A accordingto the process described in stage F of preparation A.

Stage C: 9-Aza-9,10-dimethyl-6-methoxy-2-oxa-9H-cyclopentab!fluorene-1,3-dione

The expected product is obtained according to the process described instage G of preparation A, starting with the compound described in theabove stage.

PREPARATION F 10-Nitro-2-oxacyclopenta c!phenanthrene-1,3-dione

Stage A: Dimethyl 6-nitrophenanthrene-3,4-dicarboxylate

A chilled solution of 38.8 mmol of 70% nitric acid is added dropwise toa suspension, cooled to 0° C., of 32.3 mmol of the product obtained instage A of preparation B in 120 ml of trifluoroacetic anhydride. Themedium is stirred for 3 h at 0° C. and then for 2 h at room temperature.The precipitate is then filtered off, washed with diisopropyl ether anddried.

Melting point: 180° C. with decomposition

Stage B: 6-Nitro-3-methoxycarbonylphenanthrene-4-carboxylic acid and6-nitro-4-methoxycarbonylphenanthrene-3-carboxylic acid

The mixture is prepared from the product obtained in the above stepaccording to the process described in stage B of preparation G.

Stage C: 10-Nitro-2-oxacyclopenta c!phenanthrene-1,3-dione

The product is obtained according to the process described in stage G ofpreparation A. starting with the mixture prepared in the above step.

PREPARATION G 9-Oxacyclopenta b!phenanthrene-8,10-dione

Stage A: Ethyl naphthalen-1-ylacrylate

220 ml of a 1N solution of potassium tert-butoxide in tetrahydrofuranare added dropwise to a solution of 0.219 mol ofethoxycarbonyltriphenylphosphonium bromide in 200 ml of tetrahydrofuran.The medium is stirred for 1 h at room temperature, after which asolution of 0.22 mol of naphthalene-1-carboxaldehyde in tetrahydrofuranis added dropwise. The medium is stirred for 4 h at room temperature,filtered, the solvent is evaporated off and the residue is taken up in400 ml of methylene chloride. The organic phase is washed with 100 ml ofwater, dried and concentrated. The residue is taken up in diisopropylether, the precipitate is filtered off and the expected product isobtained after concentration of the solvent.

Stage B: Naphthalen-1-ylacrylic acid

A solution of 0.2 mol of the compound prepared in the above step in 500ml of ethanol is stirred for 18 h at room temperature in the presence of250 ml of a 2N solution of sodium hydroxide. The ethanol isconcentrated, the medium is extracted with 100 ml of ethyl acetate andthe aqueous phase is acidified at 0° C. with 6N hydrochloric acidsolution. The expected product is filtered off and dried.

Melting point: 188° C.

Stage C: 2,3-Dibromonaphthalen-1-ylpropionic acid

The expected product is prepared from the acid obtained in the abovestep according to the method described in Aust. J. Chem., 16, 854, 1963.

Melting point: 197° C.

Stage D: Naphthalen-1-ylpropynoic acid

A mixture of 0.1 mol of the compound prepared in the above step in 120ml of ethanol containing 0.36 mol of potassium hydroxide is stirred atreflux for 2 h and then at room temperature for 16 h. The precipitate isfiltered off and the filtrate is concentrated. The residue is taken upin ether and the precipitate is filtered off, washed withdichloromethane and then diluted in 400 ml of water. The aqueous phaseis acidified with concentrated hydrochloric acid and the expectedproduct is filtered off, dried and recrystallized from carbontetrachloride.

Melting point: 95° C.

Stage E: 9-Oxacyclopenta b!phenanthrene-8,10-dione

The expected product is prepared from the compound prepared in the abovestep according to the method described in Aust. J. Chem., 16, 854, 1963.

Melting point: 278° C.

PREPARATION H Benzo d!benzo 2,1-b;3-4-c'!difuran-1,3-dione

Stage A: Methyl benzofuran-3-ylacetate

A mixture of 0.4 mol of coumaranone and 0.48 mol of methyl(triphenylphosphoranylidene)acetate in 1 liter of p-xylene is maintainedat reflux for 18 h. After cooling to room temperature, the solvent isevaporated off, the residue is taken up in 1 liter of ether, theprecipitate is filtered off and washed with ether, the filtrate isconcentrated and the expected product is obtained after chromatographyon silica (eluent: CH₂ Cl₂).

Stage B: 2-Benzofuran-3-ylethanol

A solution of 0.38 mol of the product prepared in the above step isadded to a suspension of 0.64 mol of LiAlH4 in 1 liter of ether stirredat 0° C. The medium is stirred for 1 h at room temperature, followed bydropwise addition of 100 ml of ethyl acetate and then 100 ml of 1N HCl.After stirring for 18 h, the medium is filtered, the filtrate isseparated out by settling and the organic phase is washed with saturatedNaCl solution and then with water. The expected product is obtainedafter drying the organic phase and evaporation of the solvent.

Stage C: 3-(2-Bromoethyl)benzofuran

The expected product is obtained from the compound prepared in the abovestep according to the procedure described in Aust. J. Chem., 44, 907,1991.

Stage D: 3-Vinylbenzofuran

The expected product is obtained from the compound prepared in the abovestep according to the procedure described in Aust. J. Chem., 44, 907,1991.

Stage E: Dimethyl 1,2-dihydrodibenzofuran-3,4-dicarboxylate

A solution of 0.2 mol of the compound prepared in the above step and 0.2mol of methyl acetylenedicarboxylate in 1 liter of degassed toluene ismaintained at reflux for 24 h under an inert atmosphere. Afterconcentration of the solvent, the expected product is obtained bychromatography on silica (eluent: CH₂ Cl₂).

Stage F: Dimethyl dibenzofuran-3,4-dicarboxylate

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage G of preparation A.

Melting point: 123° C.

Stage G: Dibenzofuran-3,4-dicarboxylic acid

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage B of preparation G.

Melting point: 260°-262° C.

Stage H : Benzo d!benzo 2,1-b;3-4-c'!difuran-1,3-dione

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage G of preparation A.

Melting point: 258° C.

PREPARATION I Benzo d!benzo 1,2-b; 3-4-c'!difuran-1,3-dione

Stage A: 2-Vinylbenzofuran

92 ml of a 1N solution of potassium tert-butoxide in tetrahydrofuran areadded dropwise to a vigorously stirred mixture at 0° C. of 68.4 mmol ofbenzofuran-2-carboxaldehyde and 92 mmol of methyltriphenylphosphoniumbromide in 200 ml of tetrahydrofuran and 150 ml of dimethylformamide.The medium is stirred for 2 h at room temperature, poured into 2 litersof ice-water and extracted with ether. After concentration of thesolvents, the residue is taken up in 1 liter of petroleum ether and theprecipitate is filtered off and washed with petroleum ether. Theexpected product is obtained by evaporation of the filtrate.

Stage B: Dimethyl dibenzofuran-1,2-dicarboxylate

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage E of preparation H.

Melting point: 126° C.

Stage C: Dibenzofuran-1-methoxycarbonyl-2-carboxylic acid anddibenzofuran-2-methoxycarbonyl-1-carboxylic acid

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage B of preparation G.

Melting point: 175°-176° C.

Stage D: Benzo d!benzo 1,2-b; 3-4-c'!difuran-1,3-dione

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage G of preparation A.

Melting point: 211° C.

PREPARATION J 2-Oxa-6-thiacyclopenta c!fluorene-1,3-dione

Stage A: Benzo b!thiophene-2-carboxaldehyde

The expected product is obtained from benzo b!thiophene according to themethod described in J.A.C.S., 74, 2396, 1952.

Melting point: 40°-41° C.

Stage B: Vinyl-2-benzo b!thiophene

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage A of preparation I

Melting point: 132°-134° C.

Stage C: Dimethyl 3,4-dihydrodibenzothiophene-1,2-dicarboxylate

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage E of preparation H.

Melting point: 129° C.

Stage D: Dimethyl dibenzothiophene-1,2-dicarboxylate

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage E of preparation A.

Stage E: 1-Methoxycarbonyldibenzothiophene-2-carboxylic acid and2-methoxycarbonyldibenzothiophene-1-carboxalylic acid

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage B of preparation G.

Melting point: 248°-250° C.

Stage F: 2-Oxa-6-thiacyclopenta c!fluorene-1,3-dione

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage G of preparation A.

Melting point: 269° C.

PREPARATION K 10-Methyl-10H-2-oxa-10-azacyclopenta a!fluorene-1,3-dione

Stage A: 1-Methyl-3-vinyl-1H-indole

The expected product is obtained from1-methyl-1H-indole-3-carboxaldehyde according to the process describedin stage A of preparation I.

Stage B: Dimethyl 9-methyl-4,9-dihydro-3H-carbazole-1,2-dicarboxylate

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage E of preparation H.

Melting point: 113° C.

Stage C: Dimethyl 9-methyl-3H-carbazole-1,2-dicarboxylate

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage E of preparation A.

Melting point: 139° C.

Stage D: 9-Methyl-1-methoxycarbonyl-3H-indole-2-carboxylic acid and9-methyl-2-methoxycarbonyl-3H-indole-1-carboxylic acid

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage B of preparation G.

Stage E: 10-Methyl-10H-2-oxa-10-azacyclopenta a!fluorene-1,3-dione

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage G of preparation A.

Melting point:>300° C.

PREPARATION L 6-Methyl-6H-2-oxa-6-azacyclopenta c!fluorene-1,3-dione

Stage A: (1-Methyl-1H-indol-2-yl)methanol

The expected product is obtained from methyl1-methyl-1H-indole-2-carboxylate according to the process described instage B of preparation H.

Melting point: 104° C.

Stage B: 1-Methyl-1H-indole-2-carboxaldehyde

A mixture of 0.1 mol of the compound prepared in the above step, 1 molof manganese oxide and 0.37 mol of sodium chloride in 500 ml of ether isstirred for 48 h at room temperature in a pressure vessel. The medium isfiltered and concentrated and the expected product is obtained bychromatography on silica (eluent: CH₂ Cl₂).

Melting point: 83° C.

Stage C: 1-Methyl-2-vinyl-1H-indole

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage A of preparation I.

Stage D: Dimethylester of9-methyl-2,9-dihydro-9H-carbazole-3,4-dicarboxylic acid

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage E of preparation H.

Melting point: 153° C.

Stage E: Dimethylester of 9-methyl-9H-carbazole-3,4-dicarboxylic acid

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage E of preparation A.

Melting point: 156° C.

Stage F: 9-Methyl-9H-carbazole-3,4-dicarboxylic acid

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage B of preparation G.

Melting point: 294° C.

Stage G: 6-Methyl-6H-2-oxa-6-azacyclopenta c!fluorene-1,3-dione

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage G of preparation A.

Melting point: >300° C.

PREPARATION M 6-Acetyl-6H-2-oxa-6-azacyclopenta c!fluorene-1,3-dione

Stage A: (1H-Indol-2-yl)methanol

The expected product is obtained from ethyl 1H-indole-2-carboxylateaccording to the process described in stage B of preparation H.

Melting point: 80° C.

Stage B: 1H-Indole-2-carboxaldehyde

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage B of preparation L.

Stage C: 2-Vinyl-1H-indole

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage A of preparation I.

Melting point: 91° C.

Stage D: Dimethyl 2,9-dihydro-1H-carbazole-3,4-dicarboxylate

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage E of preparation H.

Melting point: 249° C.

Stage E: Dimethyl 1H-carbazole-3,4-dicarboxylate

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage E of preparation A.

Melting point: 219° C.

Stage F: 3-Methoxycarbonyl-1H-carbazole-4-carboxylic acid and4-methoxycarbonyl-1H-carbazole-3-carboxylic acid

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage B of preparation G.

Stage G: 6-Acetyl-6H-2-oxa-6-azacyclopenta c!fluorene-1,3-dione

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage G of preparation A.

PREPARATION N 6-Methyl-9-nitro-6H-2-oxa-6-azacyclopentac!fluorene-1,3-dione

Stage A: Dimethyl 6-nitro-9-methyl-9H-carbazole-3,4-dicarboxylate

The expected product is obtained from the compound prepared in stage Eof preparation L according to the process described in stage A ofpreparation F.

Melting point: 234° C.

Stage B: 6-Nitro-9-methyl-9H-carbazole-3,4-dicarboxylic acid

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage F of preparation A.

Stage C: 6-Methyl-9-nitro-6H-2-oxa-6-azacyclopenta c!fluorene-1,3-dione

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage G of preparation A.

Melting point: >300° C.

PREPARATION O 6-Methyl-9-methoxy-6H-2-oxa-6-azacyclopentac!fluorene-1,3-dione

Stage A: Methyl 5-methoxy-1-methyl-1H-indolecarboxylate

100 ml of a 1N solution of potassium tert-butoxide in tetrahydrofuran isadded dropwise to a solution, cooled to -20° C., of 0,1 mol of methyl5-methoxy-1H-indolecarboxylate in tetrahydrofuran. The medium is stirredfor 30 minutes at this temperature, followed by dropwise addition of asolution of 0.1 mol of methyl iodide in tetrahydrofuran. Once theaddition is complete, the medium is warmed slowly to room temperature,stirred for 1 h at this temperature and filtered. The expected productis obtained after concentration of the solvent.

Melting point: 200° C.

Stage B: (5-Methoxy-1-methyl-1H-indole-2-yl)methanol

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage B of preparation H.

Melting point: 158° C.

Stage C: 5-Methoxy-1-methyl-1H-indole-2-carboxaldehyde

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage B of preparation L.

Melting point: 88°-90° C.

Stage D: 5-Methoxy-1-methyl-2-vinyl-1H-indole

The expected product is obtained from the compound prepared in the abovestep according to the process described in stage A of preparation I.

Melting point: 87°-89° C.

Stage E: Dimethyl6-methoxy-9-methyl-2,9-dihydro-1H-carbazole-3,4-dicarboxylate

The product is obtained from the compound prepared in the above stepaccording to the process described in stage E of preparation H.

Melting point: 245° C.

Stage F: Dimethyl 6-methoxy-9-methyl-1H-carbazole-3,4-dicarboxylate

The product is obtained from the compound prepared according to theprocess described in stage E of preparation A.

Melting point: 211° C.

Stage G: 6-Methoxy-9-methyl-1H-carbazole-3,4-dicarboxylic acid

The product is obtained from the above compound according to the processdescribed in stage F of preparation A.

Stage H: 9-Methoxy-6-methyl-6H-2-oxa-6-azacyclopentac!fluorene-1,3-dione

The product is obtained from the above compound according to the processdescribed in stage G of preparation A.

PREPARATION P 5,6-Dimethyl-6H-2-oxa-6-azacyclopenta c!fluorene-1,3-dione

Stage A: 2-Isopropenyl-1-methyl-1H-indole

The expected product is obtained from N-methyl-1H-indole according tothe method described in J.O.C., 59, (15), 4250, 1994.

Stage B: Dimethyl1,9-dimethyl-1,2-dihydro-9H-carbazole-3,4-dicarboxylate

The expected product is obtained from the product of stage A accordingto the process described in stage E of preparation H.

Stage C: Dimethyl 1,9-dimethyl-9H-carbazole-3,4-dicarboxylate

The expected product is obtained from the above product according to theprocess described in stage E of preparation A.

Stage D: 1,9-Dimethyl-9H-carbazole-3,4-dicarboxylic acid

The expected product is obtained from the above compound according tothe process described in stage F of preparation A.

Stage E: 5,6-Dimethyl-6H-2-oxa-6-azacyclopenta c!fluorene-1,3-dione

The expected product is obtained from the above compound according tothe process described in stage G of preparation A.

PREPARATION O N,N'-Bis 2-(1(R)-methylaminoethyl)ethane!-1,2-diamine

The expected product is obtained from N-(tert-butoxycarbonyl)-D-alanineand ethylenediamine according to the method described in J. Med. Chem,40, 449, 1997.

EXAMPLE 1 N,N'-Bis 2-(2-aza-1,3-dioxo-10-methoxy-cyclopentac!phenanthren-2-yl)ethyl!ethane-1,2-diamine bismethanesulfonate

A solution of 40 mmol of N-1-2-(2-aminoethylamino)ethyl!ethane-1,2-diamine in 20 ml of tolune isadded dropwise to 80 mmol of the compound described in preparation A in11 of toluene, stirred at 80° C. The reaction mixture is then maintainedat reflux for 17 h, filtered while hot and then concentrated undervacuum. The residue, taken up in 300 ml of ethanol, is stirred at refluxfor 3 h and then filtered while hot. After cooling to room temperature,the crude product is isolated by filtration and then purified bychromatography on silica. The product in base form thus collected isstirred in 450 ml of dichloromethane. A solution of two equivalents ofmethanesulphonic acid in dichloromethane is added to this medium andstirring is continued for 5 hours. The product is then filtered, washedwith ether and dried.

EXAMPLE 2 N,N'-Bis 2-(2-aza-1,3-dioxo-10-methoxy-cyclopentac!phenanthren-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation A andN-1- 3-(2-aminoethylamino)propyl!ethane-1,2-diamine.

EXAMPLE 3 1,8-Bis(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)-4-azaoctane methanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation A and4-azaoctane-1,8-diamine.

Melting point: 294° C.

EXAMPLE 4 N,N-Bis 3-(2-aza-1,3-dioxo-10-methoxycyclopentac!-phenanthren-2-yl)propyl!methylamine methanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation A andN,N-bis(3-aminopropyl)methylamine.

EXAMPLE 5 N,N'-Bis 2-(2-aza-1,3-dioxocyclopentac!phenanthren-2-yl)ethyl!-propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation B andN-1- 3-(2-aminoethyl-amino)propyl!ethane-1,2-diamine.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  60.58  4.96       6.89 7.89                                       Found       60.79  4.91       6.83 7.79                                       ______________________________________                                    

EXAMPLE 6 N,N'-Bis 2-(2-aza-1,3-dioxocyclopentac!phenanthren-2-yl)ethyl!ethane-1,2-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, replacing the product described in preparation A by theproduct described in preparation B.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  60.14  4.79       7.01 8.03                                       Found       60.32  4.89       6.97 8.02                                       ______________________________________                                    

EXAMPLE 7 N,N'-Bis 2-(2-aza-1,3-dioxonaphtho2,3-c!furan-2-yl)ethyl!ethane-1,2-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, replacing the product described in preparation A by theproduct described in preparation C.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  55.01  4.90       8.02 9.18                                       Found       54.40  4.97       7.77 8.32                                       ______________________________________                                    

EXAMPLE 8 N,N'-Bis 2-(2-aza-1,3-dioxo-8-thiadicyclopentaa,h!naphthalen-2-yl)ethyl!ethane-1,2-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, replacing the product described in preparation A by theproduct described in preparation D.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  45.50  4.22       5.59 19.18                                      Found       45.96  4.11       5.63 19.88                                      ______________________________________                                    

EXAMPLE 9 N,N-Bis 3-(2-aza-1,3-dioxo-8-thiadicyclopentaa,h!naphthalen-2-yl)-propyl!methylamine methanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation D andN,N-bis(3-aminopropyl)methylamine.

EXAMPLE 10 N,N'-Bis2-(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-methoxy-9H-cyclopentab!fluoren-2-yl)ethyl!ethane-1,2-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, replacing the product described in preparation A by theproduct described in preparation E and working in ethanol instead oftoluene.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  56.71  5.42       9.41 7.18                                       Found       56.71  5.61       9.51 7.11                                       ______________________________________                                    

EXAMPLE 11 N,N'-Bis2-(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-methoxy-9H-cyclopentab!fluoren-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation E andN-1- 3-(2-aminoethylamino)propyl!ethane-1,2-diamine and working inethanol instead of toluene.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  56.94  5.56       9.27 7.02                                       Found       57.49  5.61       9.35 7.13                                       ______________________________________                                    

EXAMPLE 12 N,N-Bis3-(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-methoxy-9H-cyclo-pentab!fluoren-2-yl)propyl!methylamine methanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation E andN,N-bis(3-aminopropyl)methylamine and working in ethanol instead oftoluene.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  63.38  5.70       8.80 4.03                                       Found       64.19  5.82       9.18 4.03                                       ______________________________________                                    

EXAMPLE 13 1,8-Bis(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-methoxy-9H-cyclopentab!fluoren-2-yl)-4-azaoctane methanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation E and4-azaoctane-1,8-diamine and working in ethanol instead of toluene.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  63.38  5.70       8.80 4.03                                       Found       62.95  5.80       8.96 4.02                                       ______________________________________                                    

EXAMPLE 14 N,N-Bis3-(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-methoxy-9H-cyclopentab!fluoren-2-yl)propyl!amine methanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation E andN,N-bis(3-aminopropyl)amine and working in ethanol instead of toluene.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  62.98  5.54       8.96 4.10                                       Found       62.91  5.63       8.78 4.17                                       ______________________________________                                    

EXAMPLE 15 N,N'-Bis3-(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-methoxy-9H-cyclo-pentab!fluoren-2-yl)propyl!ethane-1,2-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the product described in preparation E and N-2-(3-aminopropylamino)ethyl!propane-1,3-diamine, working in ethanolinstead of toluene.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  57.38  5.69       9.12 6.96                                       Found       57.08  5.66       8.64 6.50                                       ______________________________________                                    

EXAMPLE 16 N,N'-Bis 2-(2-aza-1,3-dioxo-10-hydroxycyclopentac!phenanthren-2-yl)ethyl!ethane-1,2-diamine hydrobromide

A suspension of 1 mmol of the compound of Example 1 in 40 ml of 47%hydrobromic acid is maintained at reflux for 8 hours. After cooling toroom temperature, the solid is filtered off, washed with water and takenup in refluxing ethanol for 1 h. After filtration, the expected productis obtained.

EXAMPLE 17 N,N-Bis 3-(2-aza-1,3-dioxo-10-hydroxycyclopentac!phenanthren-2-yl)propyl!methylamine hydrobromide

The expected product is obtained according to the process described inExample 16, starting with the compound of Example 4.

EXAMPLE 18 N,N'-Bis2-(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-hydroxy-9H-cyclopentab!fluoren-2-yl)ethyl!ethane-1,2-diamine dihydrobromide

The expected product is obtained according to the process described inExample 16, starting with the compound of Example 10.

EXAMPLE 19 N,N'-Bis2-(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-hydroxy-9H-cyclopentab!fluoren-2-yl)ethyl!propane-1,3-diamine dihydrobromide

The expected product is obtained according to the process described inExample 16, starting with the compound of Example 11.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     Br%                                          ______________________________________                                        Calculated  55.20  4.75       9.90 18.83                                      Found       55.11  4.44       9.73 17.53                                      ______________________________________                                    

EXAMPLE 201,8-Bis(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-hydroxy-9H-cyclopentab!fluoren-2-yl)-4-azaoctane hydrobromide

The expected product is obtained according to the process described inExample 16, starting with the compound of Example 13.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     Br%                                          ______________________________________                                        Calculated  62.24  5.09       9.30 10.62                                      Found       63.04  5.02       9.25  9.57                                      ______________________________________                                    

EXAMPLE 21 N,N'-Bis3-(2,9-diaza-9,10-dimethyl-1,3-dioxo-6-hydroxy-9H-cyclo-pentab!fluoren-2-yl)propyl!ethane-1,2-diamine

The expected product is obtained according to the process described inExample 16, starting with the compound of Example 15.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     Br%                                          ______________________________________                                        Calculated  55.70  4.91       9.74 18.53                                      Found       55.88  4.68       9.13 17.87                                      ______________________________________                                    

EXAMPLE 22 1- 2-(1,3-Dioxo-2,3-dihydro-5-nitrobenzod,e!isoquinolin-2-yl)ethyl!-3- 2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

Stage A: 2- 2-(3-Aminopropylamino)ethylamino!-5-nitrobenzod,e!isoquinoline-1,3-dione trimethanesulfonate

A solution, at 0° C., of 50 mmol of 3-nitronaphthoic anhydride in 300 mlof THF is added dropwise to a stirred solution at 0° C. of 50 mmol ofN,N'-bis(2-aminoethyl)propane-1,3-diamine in 200 ml of THF. Once theaddition is complete, the reaction mixture is stirred for 3 hours atroom temperature, for 2 hours at reflux and is then filtered while hot.The filtrate is stirred at room temperature and 150 mmol ofmethanesulfonic acid in 100 ml of THF are added dropwise. Theprecipitate is filtered off, taken up in 11 of ethanol and maintained atreflux for 2 hours. The insoluble material is filtered off and thefiltrate is cooled. The desired product is obtained after filtration, ina yield of 32%.

Stage B: 1- 2-(1,3-Dioxo-2,3-dihydro-5-nitrobenzod,e!isoquinolin-2-yl)ethyl!-3- 2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate 5 mmolof the compound described in preparation A are added portionwise to asolution of 5 mmol of the compound prepared in the above stage and 15mmol of diisopropylethylamine in 11 of ethanol stirred at roomtemperature. Once the addition is complete, the mixture is maintained atreflux for 15 hours and then filtered while hot. The cooled filtrate isfiltered and the solid is purified by chromatography on silica with theeluent 95 CH₂ Cl₂ /5 MeOH/0.1 NH₂ OH. The fractions containing theproduct are combined and concentrated, the residue is taken up in 11 ofmethylene chloride and 2 equivalents of methanesulfonic acid are added.The product is isolated by filtration.

EXAMPLE 23 1- 2-(1,3-Dioxo-2,3-dihydro-5-nitrobenzod,e!isoquinolin-2-yl)ethyl!-2- 2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)ethyl!ethane-1,2-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 22, using N,N'-bis(2-aminoethyl)ethane-1,2-diamine in stage A.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  53.00  4.52       8.31 8.37                                       Found       53.00  4.64       8.40 8.54                                       ______________________________________                                    

EXAMPLE 24 N,N'-Bis 2-(2-aza-6-oxacyclopenta c!fluorene-1,3-dion-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation I andN-1- 3-(2-aminoethylamino)propyl!ethane-1,2-diamine.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  56.05  4.58       7.07 8.09                                       Found       56.15  4.48       7.02 8.30                                       ______________________________________                                    

EXAMPLE 25 N,N'-Bis 2-(2-aza-1,3-dioxo-10-nitrocyclopentac!phenanthren-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation F andN-1- 3-(2-aminoethylamino)propyl!ethane-1,2-diamine.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  54.54  4.24       9.31 7.10                                       Found       54.73  4.27       9.24 7.24                                       ______________________________________                                    

EXAMPLE 26 N,N'-Bis 2-(2-aza-10-oxa-1,3-dioxocyclopentaa!fluoren-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation H andN-1- 3-(2-aminoethylamino)-propyl!ethane-1,2-diamine.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  56.05  4.58       7.07 8.09                                       Found       56.48  4.66       7.03 7.85                                       ______________________________________                                    

EXAMPLE 27 N,N'-Bis 2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)(1(R)-methyl)ethyl!ethane-1,2-diaminebismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation A and thecompound described in preparation Q.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  59.58  5.23       6.32 7.23                                       Found       59.77  5.26       6.15 6.99                                       ______________________________________                                    

EXAMPLE 28 N,N'-Bis 2-(2-aza-1,3-dioxocyclopentab!phenanthren-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation G andN'-1- 3-(2-aminoethyl-amino)propyl1ethane-1,2-diamine.

EXAMPLE 29 N,N'-Bis 2-(2-aza-1,3-dioxo-10-methyl-10H-pyrrolo3,4-a!carbazol-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation K andN-1- 3-(2-aminoethyl-amino)propyl!ethane-1,2-diamine.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  57.20  5.17       10.26                                                                              7.83                                       Found       57.18  5.09        9.92                                                                              8.04                                       ______________________________________                                    

EXAMPLE 30 N,N'-Bis 2-(2-aza-1,3-dioxo-6-thiacyclopentac!fluoren-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation J andN-1- 3-(2-aminoethylamino)propyl!ethane-1,2-diamine.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  53.87  4.40       6.79 15.55                                      Found       53.26  4.81       6.88 15.88                                      ______________________________________                                    

EXAMPLE 31 N,N'-Bis 2-(2-aza-1,3-dioxo-6-methyl-6H-pyrrolo3,4-c!carbazol-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation L andN-1- 3-(2-aminoethylamino)propyl!ethane-1,2-diamine.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  57.20  5.17       10.26                                                                              7.83                                       Found       57.18  5.09        9.92                                                                              8.04                                       ______________________________________                                    

EXAMPLE 32 N,N'-Bis 2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)ethyl!butane-1,4-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation A andN-1- 4-(2-aminoethylamino)butyl!ethane-1,2-diamine.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  59.58  5.23       6.32 7.23                                       Found       59.17  5.37       6.26 6.98                                       ______________________________________                                    

EXAMPLE 33 N,N'-Bis 2-(2-aza-1,3-dioxo-6H-pyrrolo3,4.c!carbazol-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, starting with the compound described in preparation M andN-1- 3-(2-aminoethyl-amino)propyl!ethane-1,2-diamine.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  56.19  4.84       10.63                                                                              8.11                                       Found       56.34  5.08       10.71                                                                              8.24                                       ______________________________________                                    

EXAMPLE 34 1- 2-(1,3-Dioxo-2,3-dihydro-5-nitrobenzod,e!isoquinolin-2-yl)ethyl!-3- 2-(2-aza-1,3-dioxo-6-methyl-6H-pyrrolo3,4-c!carbazol-2-yl)ethyl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 22, using in stage B the compound described in preparation L.

    ______________________________________                                        Elemental microanalysis:                                                                C%   H%         N%     S%                                           ______________________________________                                        Calculated  53.33  4.72       10.36                                                                              7.91                                       Found       53.80  4.70       10.46                                                                              7.88                                       ______________________________________                                    

EXAMPLE 35 N,N'-Bis 2-(2-aza-1,3-dioxo-6-methyl-9-methoxy-6H-pyrrolo-3,4-c!-carbazol)-2-yl!propane-1,3-diamine bismethanesulfonate

The expected product is obtained according to the process described inExample 1, using the compound described in preparation O and N-1-3-(2-aminoethylamino)propyl!ethane-1,2-diamine.

EXAMPLE 36 N,N'-Bis 2-(2-aza-1,3-dioxo-6-methyl-6H-pyrrolo3,4-c!carbazol-2-yl)(1-(R)-methyl)ethyl!ethane-1,2-diaminebismethanesulfonate

The expected product is obtained according to the process described inExample 1, using the compound described in preparation L and thatdescribed in preparation Q.

EXAMPLE 37 1- 2-(1,3-Dioxo-2,3-dihydro-5-nitrobenzod,e!isoquinolin-2-yl)(1-(R)-methyl)ethyl!-2-2-(2-aza-1,3-dioxo-6-methyl-6H-pyrrolo3,4-c!carbazol-2-yl)(1-(R)-methyl)ethyl!ethane-1,2-diaminebismethanesulfonate

The expected product is obtained according to the process described inExample 22, using in stage B the compound described in preparation L.

EXAMPLE 38 N,N'-Bis 2-(2-aza-1,3-dioxo-6-methyl-6H-9-nitropyrrolo3,4-c!carbazol-2-yl)(1-(R)-methyl)ethyl!ethane-1,2-diaminebismethanesulfonate

The expected product is obtained according to the process described inExample 1, using the compound described in preparation N.

EXAMPLE 39 N,N'-Bis 2-(2-aza-5,6-dimethyl-1,3-dioxo-6H-pyrrolo3,4,-c!carbazol-2-yl)(1-(R)-methyl)ethyl!ethane-1,2-diaminebismethanesulfonate

The expected product is obtained according to the process described inExample 1, using the compound described in preparation P.

EXAMPLE 40 1- 2-(2-Aza-1,3-dioxo-6-methyl-6H-pyrrolo3,4-c!carbazol-2-yl)(1-(R)-methyl)ethyl!-2-2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)(1-(R)-methyl)ethyl!ethane-1,2-diaminebismethanesulfonate

The expected product is obtained according to the process described inExample 22, using in stage A the compound described in preparation A andin stage B the compound described in preparation L.

PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE 41

in vitro proliferation

This test makes it possible to measure the anti-proliferative power of acompound in vitro by determining the concentration of product whichinhibits cell growth by 50% when compared with untreated control cells(IC₅₀). This is a colorimetric test based on cleavage, by reduction withthe mitochondrial succinate dehydrogenase of live cells, of a solubletetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, or MTT, into purple formazan crystals which are insoluble inthe culture medium. In order to ensure that they adhere fully, the cellsare inoculated at a density of 625 cells per well in 96-well plates, 24hours before being incubated at 37° C., continuously and in the presenceof a range of concentrations of the test product. After four periods ofdoubling of the cell population (determined after studying the linegrowth kinetics), the live cells are stained with MTT (1/10th of thevolume of medium is added to the wells, solution containing 5 mg/ml inPBS) for 4 hours at 37° C. At the end of this incubation, a volume equalto that of the well of a solution of SDS is added (20% SDS, 50%dimethylformamide in water, pH 4.7) which, after exposure overnight,dissolves the formazan crystals. The optical density of the medium isthen measured at 540 nm by a Titertek multiscan MCC plate reader(Labsystem). Calibration curves were produced for each of the lines fromcells inoculated at increasing densities, and made it possible toestablish a linear relationship between the number of live cells and theoptical density read.

The lines used in this test are:

the line LLC: Lewis lung carcinoma of murine origin,

the line HT-29: colon carcinoma of human origin.

The results obtained on these two lines show that the compounds of theinvention have very strong anti-proliferative power.

By way of example, the IC₅₀ of the compound of Example 22 is equal to53.60 nM on the LLC line and equal to 1.4 nM on the HT-29 line.

EXAMPLE 42

in vivo antitumor activity

The antitumor activity of the compounds of the invention was studied inNude mice. Fragments of human epidermoid carcinoma KB-3-1 were graftedsubcutaneously onto 4- to 6-week-old Nude Swiss female mice weighingfrom 20 to 22 g. When the tumors reach a diameter of about 6 mm, themice are divided among the control group and the treated group (7 miceper group) so as to obtain an identical average tumor volume in each ofthe groups. The test product is administered via the i.v. route; 1injection per day for 5 days. The tumors are measured twice a week andthe tumor volume is calculated according to the formula:volume=(length×width²)/2. The antitumor activity is evaluated by virtueof 2 parameters: the average T/C, expressed as a percentage, and the SGD(specific growth delay).

Average T/C (%) at a time t=100×(Vt/V0) average treated/ (Vt/V0) averagecontrol with Tt: tumor volume at time t; V0: tumor volume at the startof the treatment.

SGD=(Td treated--Td control)/Td control with Td=average doubling time ofthe tumor.

The results obtained with the products of the invention show that theystrongly inhibit tumor growth.

By way of example, the compound of Example 1, administered at a dose of15 mg/kg via the i.v. route for 5 days, gives the following results : 14days after the start of the treatment, the average T/C is 26% (thus 74%inhibition) and the SGD is 1.3. Furthermore, the treatment does notcause any weight loss and it is thus well tolerated.

EXAMPLE 43

Pharmaceutical composition

Preparation formula for 1000 tablets containing 10 mg doses

Compound of Example 1 10 g

Hydroxypropylcellulose 2 g

Wheat starch 10 g

Lactose 100 g

Magnesium stearate 3 g

Talc 3 g

We claim:
 1. A compound selected from those of formula (I): ##STR14## inwhich: X and Y, which may be identical or different, represent hydrogenor halogen or linear or branched (C₁ -C₆) alkyl, linear or branched (C₁-C₆) trihaloalkyl, linear or branched (C₁ -C₆) alkoxy, hydroxyl, cyano,nitro, amino, alkylamino, or dialkylamino,Z represents a linear orbranched C₄ to C₁₂ alkylene chain in which one or more --CH₂ -- groupsare optionally replaced by any one of the following atoms or groups:--NR-- (in which R represents hydrogen or linear or branched (C₁ -C₆)alkyl), --O--, --S--, --SO--, --SO₂ --, or --CONH--, A forms, with twoadjacent carbon atoms of the phenyl ring:a substituted or unsubstitutedphenyl ring, a substituted or unsubstituted naphthyl ring, a substitutedor unsubstituted tetrahydronaphthyl ring or substituted or unsubstituted1,4-dioxo-1,2,3,4-tetrahydronaphthyl, ##STR15## represents the followinggroup: ##STR16## in which: X₁ and Y₁, which may be identical ordifferent, represent hydrogen or halogen or linear or branched (C₁ -C₆)alkyl, linear or branched (C₁ -C₆) trihaloalkyl, linear or branched (C₁-C₆) alkoxy, hydroxyl, cyano, nitro, amino, alkylamino, or dialkylamino,A₁ forms, with two adjacent carbon atoms of the phenyl ring:asubstituted or unsubstituted phenyl ring, a substituted or unsubstitutednaphthyl ring, or a substituted or unsubstituted tetrahydronaphthyl ringor substituted or unsubstituted 1,4-dioxo-1,2,3,4-tetrahydronaphthylring,its optical isomers and its addition salts with apharmaceutically-acceptable acid or base.
 2. A compound of claim 1,wherein Z represents a C₄ to C₁₂ alkylene chain in which 1, 2 or 3 --CH₂-- groups are replaced by 1, 2 or 3 --NR-groups in which R representshydrogen or linear or branched (C₁ -C₆) alkyl.
 3. A compound of claim 1,wherein ##STR17## in which Z represents the C₄ -C₁₂ alkylene,X₁ and Y₁,which may be identical or different, represent hydrogen or halogen orlinear or branched (C₁ -C₆) alkyl, linear or branched (C₁ -C₆)trihaloalkyl, linear or branched (C₁ -C₆) alkoxy, hydroxyl, cyano,nitro, amino, alkylamino, or dialkylamino, A₁, forms, with two adjacentcarbon atoms of the phenyl ring:a substituted or unsubstituted phenylring,its optical isomers and its addition salts with apharmaceutically-acceptable acid or base.
 4. A compound of claim 1,selected from N,N'-bis 2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)ethyl!ethane-1,2-diamine and its addition salts witha pharmaceutically-acceptable acid.
 5. A compound of claim 1, selectedfrom N,N'-bis 2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)ethyl!propane-1,3-diamine and its addition salts witha pharmaceutically-acceptable acid.
 6. A pharmaceutical compositioncomprising as active principle an effective amount of a compound asclaimed in claim 1, together with one or morepharmaceutically-acceptable excipients or vehicles.
 7. A method fortreating a living body afflicted with a cancer selected from the groupconsisting of lung, colon, and epidermoid carcinoma comprising the stepof administering to the living body an amount of a compound selectedfrom those of formula (I): ##STR18## in which: X and Y, which may beidentical or different, represent hydrogen or halogen or linear orbranched (C₁ -C₆) alkyl, linear or branched (C₁ -C₆) trihaloalkyl,linear or branched (C₁ -C₆) alkoxy, hydroxyl, cyano nitro, amino,alkylamino, or dialkylamino,Z represents a linear or branched C₄ to C₁₂alkylene chain in which one or more --CH₂ -- groups are optionallyreplaced by any one of the following atoms or groups: --NR-- (in which Rrepresents hydrogen or linear or branched (C₁ -C₆) alkyl), --O--, --S--,--SO--, --SO₂ --, or --CONH--, A forms, with two adjacent carbon atomsof the phenyl ring:a substituted or unsubstituted phenyl ring, asubstituted or unsubstituted naphthyl ring, ora substituted orunsubstituted tetrahydronaphthyl ring or substituted or unsubstituted1,4-dioxo-1,2,3,4-tetrahydronaphthyl ring, ##STR19## represents thefollowing group: ##STR20## in which: X₁ and Y₁, which may be identicalor different, represent hydrogen or halogen or linear or branched (C₁-C₆) alkyl, linear or branched (C₁ -C₆) trihaloalkyl, linear or branched(C₁ -C₆) alkoxy, hydroxyl, cyano, nitro, amino, alkylamino, ordialkylamino, A₁ forms, with two adjacent carbon atoms of the phenylring:a substituted or unsubstituted phenyl ring, a substituted orunsubstituted naphthyl ring, or a substituted or unsubstitutedtetrahydronaphthyl ring or substituted or unsubstituted1,4-dioxo-1,2,3,4-tetrahydronaphthyl ring,its optical isomers and itsaddition salts with a pharmaceutically-acceptable acid or base, which iseffective for amelioration thereof.
 8. A method of claim 7, wherein Arepresents, with two adjacent carbon atoms of the phenyl ring, asubstituted or unsubstituted naphthyl ring.
 9. A method of claim 7,wherein Z represents a C₄ to C₁₂ alkylene chain in which 1, 2, or 3--CH₂ -- groups are replaced by 1, 2 or 3 --NR-groups in which Rrepresents hydrogen or linear or branched (C₁ -C₆) alkyl.
 10. A methodof claim 7, wherein I is ##STR21## in which: Z represents C₄ -C₁₂alkylene,X₁ and Y₁, which may be identical or different, representhydrogen or halogen or linear or branched (C₁ -C₆) alkyl, linear orbranched (C₁ -C₆) trihaloalkyl, linear or branched (C₁ -C₆) alkoxy,hydroxyl, cyano, nitro, amino, alkylamino, or dialkylamino, A₁ forms,with two adjacent carbon atoms of the phenyl ring:a substituted orunsubstituted phenyl ring, its optical isomers and its addition saltswith a pharmaceutically-acceptable acid or base.
 11. A method of claim7, wherein the compound is selected from N,N'-bis2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)ethyl!ethane-1,2-diamine and its addition salts witha pharmaceutically-acceptable acid.
 12. A method of claim 7, wherein thecompound is selected from N,N'-bis2-(2-aza-1,3-dioxo-10-methoxycyclopentac!phenanthren-2-yl)ethyl!propane-1,3-diamine and its addition salts witha pharmaceutically-acceptable acid.
 13. A pharmaceutical compositioncomprising as active principle an effective amount of a compoundselected from those of formula (I): ##STR22## in which: X and Y, whichmay be identical or different, represent hydrogen or halogen or linearor branched (C₁ -C₆) alkyl, linear or branched (C₁ -C₆) trihaloalkyl,linear or branched (C₁ -C₆) alkoxy, hydroxyl, cyano, nitro, amino,alkylamino, or dialkylamino,Z represents a linear or branched C₄ to C₁₂alkylene chain in which one or more --CH₂ -- groups are optionallyreplaced by any one of the following atoms or groups; --NR-- (in which Rrepresents hydrogen or linear or branched (C₁ -C₆) alkyl), --O--, --S--,--SO--, --SO₂ --, or --CONH--, A forms, with two adjacent carbon atomsof the phenyl ring:a substituted or unsubstituted phenyl ring, asubstituted or unsubstituted naphthyl ring, or a substituted orunsubstituted tetrahydronaphthyl ring or substituted or unsubstituted1,4-dioxo-1,2,3,4-tetrahydronaphthyl ring, ##STR23## represents thefollowing group: ##STR24## in which: X₁ and Y₁, which may be identicalor different, represent hydrogen or halogen or linear or branched (C₁-C₆) alkyl, linear or branched (C₁ -C₆) trihaloalkyl, linear or branched(C₁ -C₆) alkoxy, hydroxyl, cyano, nitro, amino, alkylamino, ordialkylamino, A₁ forms, with two adjacent carbon atoms of the phenylring:a substituted or unsubstituted phenyl ring, a substituted orunsubstituted naphthyl ring, or a substituted or unsubstitutedtetrahydronaphthyl ring or substituted or unsubstituted1,4-dioxo-1,2,3,4-tetrahydronaphthyl ring,together with one or morepharmaceutically-acceptable excipients or vehicles.